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WHO Evidence Review Group on
Intermittent Screening and Treatment (ISTp)
and ACT Treatment of Malaria in Pregnancy
Rose Gana Fomban Leke Larry Slutsker Co-Chairpersons, WHO ERG on MiP July 2015
Malaria Policy Advisory Committee Geneva, Switzerland 16-18 September 2015
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Outline
Background
Objectives
Process
Key Conclusions
Recommendations
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Background
In October 2012, on the advice of the Malaria Policy Advisory
Committee (MPAC) after the work of a dedicated evidence review
group (ERG), WHO updated the policy for IPTp with sulphadoxine-
pyrimethamine (IPTp-SP). The new policy recommends that women
living in areas of moderate to high malaria transmission should
receive IPTp-SP as early as possible in the second trimester, and at
each scheduled antenatal care (ANC) visit thereafter, with SP doses
given at least one month apart.
In 2013, the MPAC concluded that there was insufficient data to
determine at what level of SP resistance IPTp-SP should be
discontinued in the absence of an established and effective
alternative and to define the level of Plasmodium falciparum
transmission at which IPTp-SP may cease to be cost-effective from
a public health point of view.
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Background
ALTERNATIVES: several studies have been completed on the
efficacy, safety, feasibility, acceptability and cost-effectiveness of
alternative interventions to prevent the consequences of malaria in
pregnancy, including intermittent screening and treatment of malaria
in pregnancy (ISTp).
During recent years, a growing body of evidence has been
accumulated on the clinical safety of the artemisinin derivatives in
the first trimester of pregnancy, and of the efficacy of different
artemisinin-based combination therapies (ACTs) in treatment of
uncomplicated malaria in pregnancy.
To review these studies and in order to update WHO
recommendations, WHO/GMP convened an ERG with specific focus
on the efficacy of ISTp compared with IPTp and the safety of
artemisinin derivatives in early pregnancy.
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1. To review the available evidence on the efficacy, safety,
acceptability and cost-effectiveness of intermittent screening
and treatment of malaria in pregnancy (ISTp) using rapid
diagnostic tests and different antimalarial medicines as a
potential alternative strategy for intermittent preventive
treatment of malaria in pregnancy (IPTp)
2. To review the efficacy and safety data on the use of
artemisinin-based combination for the treatment of
uncomplicated malaria during pregnancy, with specific
attention to exposure in the first trimester as compared to
quinine, in view of possible revisions of current
recommendations for malaria treatment in the first trimester
of pregnancy.
Objectives of the ERG meeting
Part
Part
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Missed opportunities for delivering IPTp in 2013:
stagnant increase of IPTp uptake since 2007
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Proportion of children aged 2-10 years infected with
P. falciparum: a) 2000 and b) 2013
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ERG areas of review in relation to
potential alternatives to IPTp-SP (Part I)
1. Review all available published and unpublished reports on the efficacy,
and safety of ISTp compared to IPTp for prevention of the adverse
consequences of malaria in pregnancy.
2. Review available reports on the acceptability of ISTp under trial conditions.
3. Review results of cost-effectiveness analyses (CEA) of ISTp.
4. Review the recent evidence on the effect of submicroscopic infections
on maternal and infant outcomes.
5. Review available published and unpublished reports on the impact of SP
resistance on IPTp-SP effectiveness.
6. Review results of recently completed clinical trials evaluating the efficacy
and safety of DHA-PPQ for IPTp.
7. Based on the evidence reviewed, consider if either ISTp or IPTp with
DHA-PPQ could be recommended as a potential alternative to IPTp-SP
in some areas with high SP resistance and/or very low transmission.
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Current WHO recommendations for treatment of
uncomplicated malaria in the 1st trimester of pregnancy
…in the absence of adequate safety data on the artemisinin-
derivatives in the first trimester of pregnancy the Guideline
Development Group was unable to make recommendations
beyond reiterating the status quo.
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ERG areas of review in relation to
ACT safety in early pregnancy (Part II)
8. Review the evidence of embryotoxicity of artemisinin derivatives
from animal studies.
9. Review available published and unpublished reports on exposures
to artemisinin derivatives in the first trimester of pregnancy.
10. Review results of recent clinical trials evaluating the efficacy and
safety of different ACTs for malaria treatment in the second and
third trimester of gestation.
11. Based on the evidence reviewed, consider if the current WHO
recommendations on use of ACTs in pregnancy could be updated.
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Participants and dynamics of the ERG meeting
ERG meeting Part 1 – ISTp ERG meeting part I2 – ACT Rx
Chairpersons: Rose G. F. Leke & Larry Slutsker Rapporteur: Raquel Gonzalez
Presenters: M. Cairns, P. Deloron, M. Desai, S. Fernandes, K. Hanson, J. Hill, H. Hopkins, A. Kakuru, M. Madanitsa, C. Roper, H. Tagbor, S. Taylor, P. Walker, J. Webster
Presenters: R. Clark, U. d'Alessandro, S. Dellicour, U. Metha, E. Pelfrene, E. Sevene, A. Stergachis, T. Wells
Presenters: B. Greenwood, J. Gutman, R. Mc Gready, C. Menendez, F. Ter Kuile
Reviewers: P. Don Mathanga, P. Kremsner (part II ), M. Laufer, L. Mbuagbaw, B. Nahlen, H. Noedl (II), M. Nyunt, N. Padilla, S. Rogerson, E. Roman
Observer: D. Kyabayinze Observer: S. Duparc
WHO Secretariat: P. Alonso, A. Barette, A. Bosman, G.M. Mbemba, J. Namboze, P. Olumese, S. Schwarte
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Process
. All participants contributed to the sessions in plenary and in
working groups, but only the independent reviewers and WHO
Secretariat attended a final closed session to elaborate the
recommendations of the meeting.
DOCUMENT: REPORT
The key conclusions emerging from the topics are presented as
summarised “Key conclusions”, inboxes, at the end of the
respective sections of the report.
The main conclusions and recommendations of the meeting,
reviewed and agreed among the independent reviewers are
presented as the last section of the report and summarised at
beginning of the document.
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Pre-reads, Presentations and Discussions
ISTp compared to IPTp with SP in West and East Africa
Acceptability of ISTp under trial conditions
Cost-effectiveness of ISTp
Effects of submicroscopic infections on maternal and infant outcomes
Impact of SP resistance and malaria transmission on IPTp-SP
effectiveness
Evaluation of DHA-PPQ for IPTp
Embryotoxicity of artemisinin derivatives in animal studies
Safety of artemisinin exposure in the first trimester of pregnancy
Efficacy and safety of ACTs in the 2nd and 3rd trimester of pregnancy
General considerations on antimalarials use in pregnancy
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ISTp Compared to IPTp with SP in West and East Africa
Key conclusions
ISTp (either with SP or AL as treatment) was not inferior to IPTp with SP in preventing
third trimester maternal anemia, LBW and placental malaria in studies conducted in
areas of low SP resistance in West Africa.
However, the incidence of outpatient visits and malaria episodes during pregnancy
was higher in ISTp group compared to IPTp-SP.
The results from the trials conducted in West Africa suggest that IPTp with SP should
be continued where SP resistance is low.
ISTp with DHA-PPQ was not superior to IPTp-SP in areas of high malaria transmission
and high SP resistance of East and Southern Africa and was associated with more
malaria during pregnancy and at delivery in all gravidae and lower mean birth weight
in paucigravidae.
IPTp with SP retains some of its effectiveness in areas of high SP resistance and
should be continued in these areas.
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Acceptability of ISTp under trial conditions
Key conclusions
Overall, ISTp (either with AS-AQ or DHA-PPQ) was considered to be an
acceptable alternative to IPTp with SP both by providers and users in
trial conditions.
Quality of care of ANC services as well adherence to a three-day course of
treatment were concerns perceived by pregnant women and health care
workers respectively.
Further research would be needed to confirm these findings in larger
studies, other settings and in non-trial conditions.
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Cost-effectiveness of ISTp
Key conclusions
ISTp (with AL) was found to be more expensive and less effective for
prevention of MiP than IPTp with SP.
At the current levels of efficacy of IPTp with SP, it would not be cost-
effective to switch from IPTp-SP to ISTp-AL.
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Effects of submicroscopic infections on maternal
and infant outcomes
Key conclusions
Submiscroscopic infections, especially early in pregnancy have been associated
with maternal anemia, LBW and prematurity.
The effects of submicroscopic infections on adverse pregnancy outcomes need to
be confirmed in large longitudinal studies and in different settings.
Malaria infection prevalence is highest at the antenatal booking visit and declines
thereafter. The sensitivity of RDTs is also highest at the initial visit, in particular in
primigravidae. Thus, the use of RDTs to screen asymptomatic pregnant women
for malaria infection is likely to be most beneficial at the first antenatal visit.
Key conclusions
Submiscroscopic infections, especially early in pregnancy were associated
with maternal anaemia, LBW and prematurity.
The effects of submicroscopic infections on adverse pregnancy outcomes
need to be confirmed in large longitudinal studies and in different
settings.
Malaria infection prevalence is highest at the antenatal booking visit and
declines thereafter. The sensitivity of RDTs is also highest at the initial
visit, in particular in primigravidae. Thus, the use of RDTs to screen
asymptomatic pregnant women for malaria infection is likely to be most
beneficial at the first antenatal visit.
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Impact of SP resistance and malaria transmission
on IPTp-SP effectiveness
Key conclusions
IPTp with SP remains effective in preventing the adverse consequences of
malaria on maternal and infant outcomes, including in areas where quintuple
mutant haplotypes Plasmodium falciparum mutations to SP are highly
prevalent.
The association between dhfr 581G mutation and decreased low birth
weight in women receiving IPTp with SP compared to non-recipient of SP
reported in limited areas from Tanzania has not been observed in other sub-
Saharan countries and its potential impact on IPTp-SP effectiveness requires
further investigation.
Further research on the impact of other SP resistance markers on IPTp-
effectiveness should be done in sub-Saharan countries where IPTp-SP is used.
There is currently no evidence of a threshold level of malaria transmission
below which IPTp-SP is no longer cost-effective.
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Evaluation of DHA-PPQ for IPTp
Key conclusions
Recent studies evaluating DHA-PPQ for IPTp have found that the drug was more
efficacious than SP in reducing maternal malaria infection and anemia at
delivery, incidence of malaria during pregnancy, stillbirths and infant mortality
within 6-8 weeks.
These promising results would need to be confirmed in larger RCT involving
women in areas with similar malaria transmission and SP resistance and in areas
with different malaria transmission and SP resistance levels.
In addition, the safety of administering repeated doses of DHA-PPQ (with specific
attention to QTc prolongation) requires further investigations as well as adherence
to the required three-day regimen for each DHA-PPQ treatment dose and the
safety of DHA-PPQ co-administration with antiretrovirals in HIV-infected women.
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Embryotoxicity of artemisinin in animal studies
Key conclusions
Embryo deaths and malformations induced by artemisinin derivatives
have been reported in rats, rabbits and monkeys. The effects are dose
and time dependent.
By extrapolation of animal toxicity findings it is possible to estimate in
humans a putative sensitive embryonic period between start of week
four to the end of week ten post-conception, or from the start of week
six to the end of week 12 post LMP.
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Safety of artemisinin in the first trimester of pregnancy
Key conclusions
Updated evidence on the safety of artemisinin indicates that ACT exposure in first
trimester of pregnancy does not increase the risk of miscarriage, stillbirths or
major congenital malformations compared to quinine.
Women treated with an artemisinin anytime during first trimester were at similar or
lower risk of miscarriage compared to those treated with oral quinine.
Based on the available updated evidence, the first line treatment of uncomplicated
malaria in the first trimester of pregnancy should be revised to include ACTs as
therapeutic option.
Most of the data of artemisinin exposure in the first trimester of pregnancy are
from AL exposure and consequently, more safety data are needed with other ACTs
There is a need for continued monitoring and pharmacovigilance of drug exposure
in early pregnancy, including more information on congenital malformations.
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Post-ERG meeting updated analyses
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Risk of miscarriage and stillbirth with artemisinin and quinine
exposures in early pregnancy.
Post-ERG meeting updated analyses
The upper limit of the 95% CI of the hazard ratio rule out a 1.55-fold or greater
increase in risk of miscarriage and a 4.63-fold or greater increase in risk of stillbirth.
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Risk detectable for major malformations
Post-ERG meeting updated analyses
Minimum level of increase in relative risks for congenital malformations that can
be ruled out, according to the number of confirmed exposed pregnancies for
each artemisinin treatment type (Power 80% and one-sided α=0.05).
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Efficacy and safety of ACTs in the 2nd and 3rd
trimester of pregnancy
Key conclusions
Data on ACTs use for treatment of clinical uncomplicated malaria in
second and third trimesters of pregnancy indicate that they are safe in
terms of pregnancy outcomes and efficacious to clear Plasmodium
parasites (especially DHA-PPQ).
ACTs can be thus considered a safe and efficacious option for treatment of
clinical uncomplicated malaria in women in the second and third trimester
of gestation.
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General considerations on antimalarials use
in pregnancy
Key conclusions
More studies in HIV-infected pregnant women are needed, including
evaluation of mother to child transmission and drug interactions
between antimalarials and antiretrovirals.
WHO experience
In 2012, WHO recommended the use of efavirenz as first line treatment of HIV
infection in pregnancy despite pre-clinical data showing embryotoxicity, based on
comprehensive reviews of safety data in pregnant women and programmatic
superiority to standard of care. A similar approach could be followed to support an
updated WHO recommendation of ACT use in first trimester of pregnancy.
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Draft recommendations (I)
IPTp with SP remains highly cost-effective in preventing the adverse
consequences of malaria on maternal and fetal outcomes, and should
thus be aggressively scaled-up in line with the current WHO
recommendations. IPTp with SP also remains effective in areas
where quintuple mutant haplotypes of Plasmodium falciparum to SP
are highly prevalent.
The association between sextuple mutant haplotypes of P. falciparum
and decreased low birth weight (LBW) reported in limited areas in
Tanzania with very high SP resistance in the context of observational
studies using retrospective information about the assignment of SP,
has not been observed in other sub-Saharan countries in the context
of randomised controlled trials with SP, and requires further
investigation. In these limited geographic areas with very high SP
resistance, the benefits and cost-effectiveness of adding at the first
ANC visit a single RDT screening and treatment to the continued
provision of IPTp with SP, should be evaluated in pilot studies.
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Draft recommendations (II)
There is currently no evidence of a threshold level of malaria
transmission below which IPTp-SP is no longer cost-effective.
Therefore, in areas where IPTp with SP is implemented and
transmission reduced to low levels as a result of successful control
strategies, WHO recommends continued implementation until the
area has been targeted for malaria elimination by the national
programme.
Recent studies have shown that intermittent screening and
treatment (IST) with RDTs and ACTs of pregnant women at ANC
resulted in a higher proportion of maternal infections and clinical
malaria during pregnancy and lower mean birth weight compared
with IPTp-SP. Further, being less cost-effective than IPTp with SP,
ISTp with the currently available RDTs should not be recommended
as an alternative to IPT-SP.
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Draft recommendations (II)
Recent studies have shown that IPTp with dihydroartemisinin-
piperaquine (DHA-PPQ) did not reduce low birth weight compared
to IPTp with SP, but was more efficacious in reducing maternal
malaria parasitemia and anemia at delivery, incidence of malaria
infection and clinical malaria during pregnancy, stillbirths and early
infant mortality within 6-8 weeks. More research is needed to
evaluate the impact of DHA-PPQ for IPTp on LBW, safety of
repeated doses and adherence to the required three-day regimen.
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Draft recommendations (III)
New evidence from 1025 pregnancies with confirmed artemisinin
exposure in first trimester indicate that artemisinins do not increase the
risk of miscarriage, stillbirths or major congenital malformations
compared to women with malaria treated with non-artemisnin
regimens. Moreover, comparison of carefully documented and
prospectively collected safety data on women exposed to only
artemisinin-based treatment with those collected on women exposed to
only quinine in the first trimester of pregnancy showed that artemisinin
was associated with a significantly reduced rate of miscarriage
compared to quinine. Therefore, the WHO recommendations for the
treatment of clinical uncomplicated malaria episodes in women in the
first trimester of pregnancy should be updated as follows: “Treat
pregnant women with uncomplicated P. falciparum malaria with either
the first line ACT for three days or quinine and clindamycin for seven
days”. Artemether-lumefantrine (AL) should be the preferred ACT, as
most of the available data derive from AL exposure.
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Draft recommendations (III)
Although the evidence regarding the safety of ACTs in early
pregnancy has been strengthened by the recent review, there is the
need for continued monitoring of drug safety, birth outcomes and
neonatal mortality. Moreover, potential drug-drug interactions in HIV-
infected pregnant women who are taking antiretrovirals and receive
antimalarials as well as the risk of mother to child transmission
should also be monitored.